PROTEOMICS SHARED RESOURCE (PSR): PROJECT SUMMARY The Siteman Cancer Center (SCC) Proteomics Share Resource (PSR) has been a major contributor to the emerging field of proteogenomics with a track record of high impact publications and external funding. The PSR is poised to continue as leaders in the field in the next five years, using reproducible and repeatable deep-scale proteomics (? 10,000 genes) and phosphoproteomics (? 37,000 sites) and the harmonized protocol that was co- developed with the National Cancer Institute Clinical Proteomics Tumor Analysis Consortium (CPTAC). Studies are underway with comprehensively characterized Acute Myeloid Leukemia and pre/post treatment ovarian cancer cohorts (Aim 1). In the current project period, PSR has developed high-precision assays for absolute quantification (copies/cell) of 361 of the 526 protein kinases in the human kinome using CPTAC guidelines for validation toward FDA approval and clinical utility. The PSR proposes to have complete coverage of the human kinome by 2023 and to continue applying and developing cancer-type specific panels for PDX and human drug trials (Aim 2). Proteomics is on the cusp of next generation instrumentation that will lead to quantification of all expressed proteins and generate wider coverage of post-translational modifications. Using these new platforms, and in collaboration with the recently-established Washington University School of Medicine (WUSM) Mass Spectrometry Center, the PSR will develop new services for SCC members and increase the value and utility of proteogenomic analysis in support of SCC research programs (Aim 3). Future directions for the next project period include an emphasis on expanding services and enhancing cross-core interface to improve user experience and interpretation of data. PSR will continue to develop software in collaboration with the bioinformatic resources of the Genome Technology Access Center (GTAC) and The McDonnell Genome Institute (MGI) with the overarching goal of providing tools for more efficient interpretation of high-density proteogenomic data. WUSM recently recruited two faculty members who will contribute to PSR plans to expand services in the next project period. Ben Major (MCBP), from the Lineberger Comprehensive Cancer Center at the University of North Carolina, will serve as PSR Faculty Advisor and actualize expansion of PSR services in the area of proximity-labeling mass spectrometry for high-specificity characterization of intracellular complexes in cancer biology. With the successful recruitment of Dennis Goldfarb to WUSM and his agreement to collaborate on development of new MS and bioinformatics tools for proteogenomics, PSR will offer members new capabilities for facile discovery and hypothesis generation.